MECHANISMS OF HOX GENE REGULATION BY MLL

Project: Research project

Description

DESCRIPTION: Rearrangement of the mixed lineage leukemia gene (MLL, HRX, ALL-1) are associated with aggressive acute lymphoblastic leukemia in infants as well as acute myelogenous leukemia which often arises secondary to therapy with topoisomerase II inhibitors. MLL is the human homolog of Drosophila trithorax, a chromatic-associated protein that maintains homeobox (Hox) gene expression by blocking transcriptional repression by Polycomb group (Pc-G) proteins. Over twenty different MLL translocation partners have been identified which in general share little sequence homology. Possible mechanisms for MLL-mediated leukemogenesis include loss of function from truncation of the MLL protein, a gain of function mechanism produced by the chimeric protein, or a combination of loss of function and gain of function mechanisms. Given the ability of MLL to regulate Hox gene expression and the apparent importance of Hox genes in hematopoiesis, it is likely that deregulation of Hox expression by MLL fusion proteins plays a central role in leukemogenesis. Studying how MLL and MLL fusion proteins regulate these downstream target genes may provide important insights into the mechanism of MLL-mediate leukemogenesis. To this end the proposed research will 1) define domains of MLL that are required for Hox gene regulation, 2) identify the cis-acting DNA sequences that are required for MLL action and map these relative to sequences required for mammalian Pc-G repression, 3) identify Hox genes regulated by MLL in specific lineages, and 4) examine the effect of MLL fusion proteins on hematopoiesis and Hox gene expression.
StatusFinished
Effective start/end date7/1/986/30/08

Funding

  • National Institutes of Health: $258,268.00
  • National Institutes of Health: $312,433.00
  • National Institutes of Health: $284,113.00
  • National Institutes of Health: $292,598.00
  • National Institutes of Health: $314,584.00
  • National Institutes of Health: $270,236.00
  • National Institutes of Health: $327,722.00
  • National Institutes of Health
  • National Institutes of Health: $265,453.00
  • National Institutes of Health: $275,162.00

Fingerprint

Homeobox Genes
Leukemia
Genes
Proteins
Gene Expression
Hematopoiesis
Gene Fusion
Polycomb-Group Proteins
Acute Myeloid Leukemia
Topoisomerase II Inhibitors
Histone Code
Drosophila
Histones
Sequence Homology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acetylation

ASJC

  • Medicine(all)